The present invention relates to certain thiazolopyrimidine compounds, processes and intermediates used in their preparation, pharmaceutical compositions containing them and their use in therapy.
The compound 2,7-diamino-5-methylmercapto-thiazolo[4,5-d]pyrimidine is known from J. Amer. Chem. Soc., 73, 4226-4227 (1951).
Chemokines play an important role in immune and inflammatory responses in various diseases and disorders, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The chemokine superfamily can be divided into two main groups exhibiting characteristic structural motifs, the Cys-X-Cys (C-X-C) and Cys-Cys (C-C) families. These are distinguished on the basis of a single amino acid insertion between the NH-proximal pair of cysteine residues and sequence similarity.
The C-X-C chemokines include several potent chemoattractants and activators of neutrophils such as interleukin-8 (IL-8) and neutrophil-activating peptide 2 (NAP-2).
The C-C chemokines include potent chemoattractants of monocytes and lymphocytes but not neutrophils such as human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2 and MCP-3), RANTES (Regulated on Activation, Normal T Expressed and Secreted), eotaxin and the macrophage inflammatory proteins 1xcex1 and 1xcex2 (MIP-1xcex1 and MIP-1xcex2).
Studies have demonstrated that the actions of the chemokines are mediated by subfamilies of G protein-coupled receptors, among which are the receptors designated CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10, CXCR1, CXCR2, CXCR3 and CXCR4. These receptors represent good targets for drug development since agents which modulate these receptors would be useful in the treatment of disorders and diseases such as those mentioned above.
In accordance with the present invention, there is therefore provided a compound of general formula 
wherein R1 represents a hydrogen atom, or a group xe2x80x94NR3R4;
R3 and R4 each independently represent a hydrogen atom, or a 4-piperidinyl, C3-C6 to cycloalkyl or C1-C8 alkyl group, which latter two groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, xe2x80x94SR10, xe2x80x94SO2R10, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, morpholinyl, C1-C4 alkyl, C3-C6 cycloalkyl, tetrahydrofuranyl and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94NR8COR9, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, C1-C6 alkyl and trifluoromethyl groups, or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from 
xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR10, xe2x80x94NR8COR9, and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and xe2x80x94NR11R12 and xe2x80x94OR7 groups;
X represents a group xe2x80x94OH or xe2x80x94NR13R14;
R13 and R14 each independently represent a hydrogen atom, a 4-piperidinyl group optionally substituted by a C1-C4 alkylphenyl substituent group, or a C3-C7 carbocyclic, C1-C8 alkyl, C2-C6 alkenyl or C2-C6 alkynyl group, which latter four groups may be optionally substituted by one or more substituent groups independently selected from halogen atoms and xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, xe2x80x94SR10, xe2x80x94SO2R10, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, morpholinyl, C1-C4 alkyl, C3-C6 cycloalkyl and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one or more substituents independently selected from halogen atoms and cyano, nitro, xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94NR8COR9, xe2x80x94SO2NR5R6, NR8S2R9, C1-C6 alkyl and trifluoromethyl groups,
or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one or more substituent groups independently selected from xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and phenyl, xe2x80x94NR11R12 and xe2x80x94OR7 groups;
R2 represents a C1-C6 alkyl or C2-C6 alkenyl group optionally substituted by a phenyl or phenoxy group, wherein the phenyl or phenoxy group may itself be optionally substituted by one or more substituents independently selected from halogen atoms and nitro, C1-C6 alkyl, trifluoromethyl, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94SR10, xe2x80x94NR15R16 and phenyl groups;
R5 and R6 each independently represent a hydrogen atom or a C1-C6 alkyl or phenyl group, each of which may be optionally substituted by one or more substituent groups independently selected from halogen atoms, phenyl, xe2x80x94OR17 and xe2x80x94NR15R16, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms, which ring system may be optionally substituted by one or more substituent groups independently selected from phenyl, xe2x80x94OR17, xe2x80x94COOR17, xe2x80x94NR15R16, xe2x80x94CONR15R16, xe2x80x94NR15COR16, xe2x80x94SONR15R16, and C1-C6 alkyl optionally substituted by one or more substituents independently selected from halogen atoms and xe2x80x94NR15R16 and xe2x80x94OR17 groups;
R7 and R9 each independently represent a hydrogen atom or a C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or phenyl group, each of which may be optionally substituted by one or more (e.g. one, two, three or four) substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine), phenyl, xe2x80x94OR17 and xe2x80x94NR15R16; and
each of R8, R10, R11, R12, R15, R16 and R17 independently represents a hydrogen atom or a C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) or phenyl group; with the proviso that when R1 and X both represent xe2x80x94NH2, then R2 does not represent a methyl group;
or a pharmaceutically acceptable salt or solvate thereof.
In the context of the present specification, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent group may be linear or branched. Where a substituent in an alkenyl group is a phenoxy group, the phenoxy group is not attached to an unsaturated carbon atom. A carbocyclic group is a saturated hydrocarbyl group that may be monocyclic or polycyclic (e.g. bicyclic). Similarly, a saturated heterocyclic ring system may be monocyclic or polycyclic (e.g. bicyclic).
In formula (I) above, the group R1 represents a hydrogen atom, or a group xe2x80x94NR3R4. Particularly advantageous compounds of formula (I) are those in which R1 represents a group xe2x80x94NR3R4.
Preferably, R3 and R4 each independently represent a hydrogen atom, or a 4-piperidinyl, C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) or C1-C8, particularly C1-C6, alkyl group (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl or octyl), which latter two groups may be optionally substituted by one, two, three or four substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, xe2x80x94SR10, xe2x80x94SO2R10, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, morpholinyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl), C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), tetrahydrofuranyl and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one, two, three or four substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and cyano, nitro, xe2x80x94NR5R6, CONR5R6, xe2x80x94OR7, xe2x80x94NR8COR9, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) and trifluoromethyl groups,
or R3 and R4 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one, two or three substituent groups independently selected from 
xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR10, xe2x80x94NR8COR9, and C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by one, two or three substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and xe2x80x94NR11R12 and xe2x80x94OR7 groups.
Particularly advantageous compounds of formula (I) are those in which R3 and R4 each independently represent a hydrogen atom, or a C1-C6 alkyl group substituted by a xe2x80x94CONR5R6 or imidazolyl (e.g. 1H-imidazol-4-yl) group.
Preferably, R2 represents a C1-C6 alkyl or C2-C6 alkenyl group optionally substituted by a phenyl or phenoxy group, wherein the phenyl or phenoxy group may itself be optionally substituted by one, two, three or four substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and nitro, C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl), trifluoromethyl, xe2x80x94OR7, xe2x80x94C(O)R7, xe2x80x94SR10, xe2x80x94NR15R16 and phenyl groups.
Particularly advantageous compounds of formula (I) are those in which R2 represents a C1-C6 alkyl group optionally substituted by a phenyl, halophenyl (e.g. 2,3-difluorophenyl) or xe2x80x94OR7 (e.g. phenoxy) group.
Preferably, R5 and R6 each independently represent a hydrogen atom or a C1-C6, particularly C1-C4, alkyl or phenyl group, each of which may be optionally substituted by dione, two, three or four substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine), phenyl, xe2x80x94OR7 and xe2x80x94NR15R16, or R5 and R6 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system optionally comprising a further heteroatom selected from oxygen and nitrogen atoms (e.g. one or two oxygen and/or nitrogen atoms), which ring system may be optionally substituted by one, two or three substituent groups independently selected from phenyl, xe2x80x94OR17, xe2x80x94COOR17, xe2x80x94NR15R16, xe2x80x94CONR15R16, xe2x80x94NR15COR16, xe2x80x94SONR15R16, and C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by one, two or three substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and xe2x80x94NR15R16 and xe2x80x94OR17 groups.
Preferably, R13 and R14 each independently represent a hydrogen atom, a 4-piperidinyl group optionally substituted by a C1-C4 alkylphenyl substituent group, or a C3-C7 carbocyclic, C1-C8, particularly C1-C6, alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, heptyl or octyl), C2-C6 alkenyl (ethenyl, propenyl, butenyl, pentenyl or hexenyl) or C2-C6 alkynyl (ethynyl, propynyl, butynyl, pentynyl or hexynyl) group, which latter four groups may be optionally substituted by one, two, three or four substituent groups independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, xe2x80x94SR10, xe2x80x94SO2R10, xe2x80x94SO2NR5R6, xe2x80x94NR8SO2R9, morpholinyl, C1-C4 alkyl (e.g. methyl, ethyl, propyl, isopropyl, butyl or t-butyl), C3-C6 cycloalkyl (i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), and aryl groups, wherein an aryl substituent group may be a phenyl, naphthyl, thienyl, pyridinyl, imidazolyl or indolyl group, each of which may be optionally substituted by one, two, three or four substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and cyano, nitro, xe2x80x94NR5R61 xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94NR8COR9, xe2x80x94SO2NR5R6, NR8SO2R9, C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) and trifluoromethyl groups, or R13 and R14 together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring system, which ring system may be optionally substituted by one, two or three substituent groups independently selected from xe2x80x94NR5R6, xe2x80x94CONR5R6, xe2x80x94OR7, xe2x80x94COOR7, xe2x80x94NR8COR9, and C1-C6, particularly C1-C4, alkyl (e.g. methyl, ethyl, propyl, butyl, pentyl or hexyl) optionally substituted by one, two or three substituents independently selected from halogen atoms (e.g. fluorine, chlorine, bromine or iodine) and phenyl, xe2x80x94NR11R12 and xe2x80x94OR7 groups;
Particularly advantageous compounds of formula (I) are those in which one of R13 and R14 represents a hydrogen atom and the other of R13 and R14 represents a C1-C6 alkyl group substituted by an xe2x80x94OR7 group, e.g. xe2x80x94CH(CH2CH3)CH2OH, xe2x80x94C(CH3)2CH2OH or CH(CH2CH(CH3)2)CH2OH.
Particularly preferred compounds of the invention include:
(2R)-2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(S)-2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-Amino-5-[[(2,3-difuorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
5-[[(3-Phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
(xc2x1)-2-[[2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-[[2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl]amino]ethanol,
5-(Pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[3-(Dimethylamino)propyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(Diethylamino)ethyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(Dimethylamino)ethyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[(3-Hydroxypropyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(Acetylamino)ethyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
(xc2x1)-2-[(2,3-Dihydoxypropyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(4-Morpholinyl)ethyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[(2-Methoxyethyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[(1-Methylethyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-(Cyclopropylamino)-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
(xc2x1)-2-[(2-Hydoxypropyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[(2-Hydroxy-2-methylpropyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[(2-Hydroxyethyl)amino]-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7(4H)-one,
(2S,3R)-3-Hydroxy-2-[(7-oxo-5-(pentylthio)-4H-thiazolo[4,5-d]pyrimidin-2-yl]amino)butanamide,
N7-[3-(Dimethylamino)propyl]-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-[2-(Diethylamino)ethyl]-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-[2-(Dimethylamino)ethyl]-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
3-[(2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl)amino]-1-propanol,
N7-Cyclohexyl-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
(xc2x1)-3-[(2-Amino-5-((phenylmethyl)thio)thiazolo[4,5-d]pyrimidin-7-yl)amino]-1,2-propanediol,
N7-(2-Methoxyethyl)-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
5-(Pentylthio)-N7-propylthiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-Cyclopentyl-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-Cyclopropyl-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-(2-Methylpropyl)-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
(xc2x1)-1-[(2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl)amino]-2-propanol,
(exo)-N7-Bicyclo[2.2.1]hept-2-yl-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
2-[2-[[2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl]amino]ethoxy]ethanol,
(xc2x1)-N7-(2-Methylbutyl)-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
1-[[2-Amino-5-(pentylthio)thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-2-propanol,
N7-[(2-Aminophenyl)methyl]-5-(pentylthio)thiazolo[4,5-d]pyrimidine-2,7-diamine,
2-Amino-5-[(2-phenoxyethyl)thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
(E)-2-Amino-5-[(3-phenyl-2-propenyl)thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[3-[2,4-bis(1,1-dimethylethyl)phenoxy]propyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[[(4-trifluoromethyl)phenyl]methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3,5-dichlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2,4-dichlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3,4-dichlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3.5-dibromophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2-nitrophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2-fluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2-iodophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3-chlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3-chlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(4-chloro-2-nitrophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3-chloro-4-methoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2,3-dichlorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3,5-difluorophenyl)methyl]thio]thiazolo[4,54-d]pyrimidin-7(4H)-one,
2-Amino-5-[[[(2,4-bis(trifluoromethyl)phenyl]methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2-bromophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2,3,4-trifuorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(3-bromophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-Amino-5-[[(2-fluoro-3-methylphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
3-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2,2-dimethyl-1-propanol,
(xc2x1)-xcex1-[[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]methyl]benzenemethanol,
(R)-xcex2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]benzenepropanol,
2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]ethanol,
(2R)-2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentanol,
(xc2x1)-1-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
(xc2x1)-5-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-chlorobenzenepropanol,
(xc2x1)-3-[[2-Amino[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1,2-propanediol,
2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]propylamino]ethanol,
(xc2x1)-1-[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-pyrrolidinol,
(xc2x1)-1-[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-piperidinol,
1-[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-piperidinol,
3-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2,2-dimethyl-1-propanol,
(xc2x1)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(xc2x1)-xcex1-[[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl)-2-amino]methyl]benzenemethanol,
4-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
6-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-hexanol,
4-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]cyclohexanol,
(R)-xcex2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,54-d]pyrimidin-7-yl]amino]benzenepropanol,
(xc2x1)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]tho]thiazolo[4,5-d]pyrimidin-7-yl]amino]ethanol,
(2R)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methylpentanol,
(xc2x1)-1-Amino-3-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
(xc2x1)-1-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
2-[[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]methyl]-2-ethyl-1,3-propanediol,
(xc2x1)-xcex2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-chlorobenzenepropanol,
(xc2x1)-3-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1,2-propanediol,
2-[[2-[[2-Amino-5-[[(3-phonoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]ethyl]amino]ethanol,
3-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-xcex1-[[(2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]methyl]-3,4-dichlorobenzenepropanol,
1-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-2-propanol,
2-[2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]ethoxy]ethanol,
5-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
(2S)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-(methylthio)-1-butanol,
2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]butylamino]ethanol,
2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]propylamino]ethanol,
2,2xe2x80x2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]imino]bisethanol,
2-[[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-(2-hydroxyethyl)amino]methyl]phenol,
3-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-(2-hydroxyethyl)amino]-1-propanol,
(xc2x1)-1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-pyrrolidinol,
(trans)-1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-hydroxy-L-proline phenylmethyl ester,
(xc2x1)-1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-piperidinemethanol,
(xc2x1)-1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-piperidinol,
(2S)-1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-2-pyrrolidinemethanol,
1-[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-piperidinol,
(2R)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(2S)-2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(2R)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1,3-propanediol,
2-[[2-Amino-5-[[(3-phenoxyphenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-2-propanol,
5-[[(2,3-Difluorophenyl)methyl]thio]-N7-(2-fluoroethyl)thiazolo[4,5-d]pyrimidine-2,7-diamine,
(1R-trans) 2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-cyclopentanol,
(1S-trans) 2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-cyclopentanol,
2-[[2-Amino-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-Methyl-2-[[2-(methylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[5-[((2,3-Difluorophenyl)methyl]thio]-2-[(phenylmethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
5-[[(2,3-Difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7(4H)-one,
(xc2x1)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(1S,2S)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-cyclohexanol,
(xc2x1)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-ethanol,
(2R)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
(xc2x1)-1-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1,3-propanediol,
1-[[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]methyl]-cyclohexanol,
(2R)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl](2-aminoethyl)amino]-1-ethanol,
2-[2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]ethoxy]-1-ethanol,
(xcex1S)-xcex1-(1R)-1-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]methylamino]ethyl]-benzenemethanol,
1-[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-piperidinol,
5-[[(2,3-Difluorophenyl)methyl]thio]-N7-ethyl-thiazolo[4,5-d]pyrimidine-2,7-diamine,
5-[[(2,3-Difluorophenyl)methyl]thio-N7-(2-propenyl)-thiazolo[4,5-d]pyrimidine-2,7-diamine,
(1S,2S)-2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-phenyl-1,3-propanediol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1,3-propanediol,
2-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-ethanol,
(xc2x1)-5-[[(2,3-Difluorophenyl)methyl]thio]-N7-(2-methoxy-1-methylethyl)-thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-Cyclopropyl-5-[[(2,3-difluorophenyl)methyl]thio]-thiazolo[4,5-d]pyrimidine-2,7-diamine,
(xc2x1)-2-[[2-Amino-5-[(2,3-difluorophenyl)methyl]thio]-thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
4-[[2-Amino-5-[[(2,3-difluorophenyl)methyl]thio]-thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
5-[[(2,3-Difluorophenyl)methyl]thio]-N7-[2-(1H-imidazol-4-yl)ethyl]-thiazolo[4,5-d]pyrimidine-2,7-diamine,
(xc2x1)-N-[5-[[(2,3-Difluorophenyl)methyl]thio]-7-[(2-hydroxy-1,1-dimethylethyl)amino]thiazolo[4,5-d]pyrimidin-2-yl]-serine, methyl ester,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(1-methylethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-(ethylamino)thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[2-(1H-indol-3-yl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(1-naphthalenylmethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(1,2-diphenylethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(2,2,2-trifluoroethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[(3,4,5-trimethoxyphenyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(1,1-dimethylethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(4-methylcyclohexyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-7-[(2-hydroxy-1,1-dimethylethyl)amino]thiazolo[4,5-d]pyrimidin-2-yl]amino]-acetamide,
2-[[2-[[2-(4-Aminophenyl)ethyl]amino]-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(2-fluoroethyl)amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-(Cyclopropylamino)-5-[[(2,3-difluorophenyl)methyl]thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(xc2x1)-2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-7-[(2-hydroxy-1,1-dimethylethyl)amino]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1-pentanol,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[2-(2-hydroxyethoxy)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
N-[5-[[(2,3-Difluorophenyl)methyl]thio]-6,7-dihydro-7-oxo-thiazolo[4,5-d]pyrimidin-2-yl]-DL-serine, methyl ester,
5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(1-methylethyl)amino]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[2-(1H-indol-3-yl)ethyl]amino]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[5-[[(2,3-Difluorophenyl)methyl]thio]-6,7-dihydro-7-oxo-thiazolo[4,5-d]pyrimidin-2-yl]amino]-acetamide,
2-[[2-(4-Aminophenyl)ethyl]amino]-5-[[(2,3-difuorophenyl)methyl]thio]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
5-[[(2,3-Difluorophenyl)methyl]thio]-2-[(2-fluoroethyl)amino]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
5-[[(2,3-Difluorophenyl)methyl]thio]-2-[[2-(2-hydroxyethoxy)ethyl]amino]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
2-[[2-(Cyclohexylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[(1,1-Dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
N-[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]-DL-alanine, methyl ester,
4-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-cyclohexanol,
2-Methyl-2-[[2-[(4-phenylbutyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-Methyl-2-[[5-[(phenylmethyl)thio]-2-[[(tetrahydro-2-furanyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-Methyl-2-[[2-[(1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[2-(4-Aminophenyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
N-[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]-L-valine, ethyl ester,
(2S)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-4-methyl-pentanamide,
2-Methyl-2-[[2-[(2-phenylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[(4-Aminophenyl)methyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-Methyl-2-[[5-[(phenylmethyl)thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[(2-Fluoroethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-Methyl-2-[[2-[[(3-nitrophenyl)methyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xcex1R)-xcex1-[(1S)-1-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-benzenemethanol,
2-Methyl-2-[[5-[(phenylmethyl)thio]-2-[[(3,4,5-trimethoxyphenyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-Methyl-2-[[2-[(1R-trans)-(2-phenylcyclopropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[2-(1H-Indol-3-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[(1,1-Dimethylpropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(xc2x1)-2-Methyl-2-[[2-[(1-methylbutyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-2-Methyl-2-[[2-[(1-methylhexyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[(2-Aminophenyl)methyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1,3-propanediol,
2-[[2-[[2-(Ethylthio)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(2S)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-3,3-dimethyl-1-butanol,
(xcex1S)-xcex1-[(1R)-1-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-2-methoxyethyl]-benzenemethanol,
2-[[2-(Ethylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[[[3-Fluoro-5-(trifluoromethyl)phenyl]methyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(xc2x1)-2-Methyl-2-[[2-[(1-methylpropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[[2-[[(4-Methoxyphenyl)methyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[(2-Hydroxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol, 2-[[2-[(Diphenylmethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(2S)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1-butanol,
2-[[2-[(2,2-Diethoxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
4-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1-butanol,
(1S,2S)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-cyclohexanol,
(xc2x1)-2-[[2-[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
2-[[2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(xc2x1)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1-pentanol,
2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-acetamide,
(xc2x1)-2-[[2-[[1-(4-Fluorophenyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-propanol,
(1R,2S)-2-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-cyclohexanol,
(xcex1S)-xcex1-[(1R)-1-[[7-[(2-Hydroxy-1,1-dimethylethyl)amino]-5-[(phenylmethyl )thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-benzenemethanol,
(xc2x1)-2-[[2-(Methylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-4-Methyl-2-[[2-(methylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
N-[2-(Methylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-L-serine, ethyl ester,
(xc2x1)-2-[[5-[(Phenylmethyl)thio]-2-[[(tetrahydro-2-furanyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(xc2x1)-2-[[5-[(Phenylmethyl)thio]-2-[[(tetrahydro-2-furanyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-4-Methyl-2-[[5-[(phenylmethyl)thio]-2-[[(tetrahydro-2-furanyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
N-[5-[(Phenylmethyl)thio]-2-[[(tetrahydro-2-furanyl)methyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]-L-serine, ethyl ester,
(xc2x1)-2-[[2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-4-[2-[[7-[[1-(Hydroxymethyl)propyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-benzenesulfonamide,
(xc2x1)-4-[2-[[7-[[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-benzenesulfonamide,
4-[2-[[7-[[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-benzenesulfonamide,
(xc2x1)-4-[2-[[7-[(2-Hydroxypropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-1-yl]amino]ethyl]-benzenesulfonamide,
N7-Ethyl-N2-[2-(1H-imidazol-4-yl)ethyl]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidine-2,7-diamine,
N2-[2-(1H-Imidazol-4-yl)ethyl]-5-[(phenylmethyl)thio]-N7-(3-pyridinylmethyl)thiazolo[4,5-d]pyrimidine-2,7-diamine,
(xc2x1)-2-[[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(xc2x1)-2-[[2-[(2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-2-[[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
(xc2x1)-1-[[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
5-[[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
1-[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-(phenylmethyl)-4-piperidinol,
(xc2x1)-1-[2-[[2-(1H-Imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-piperidinecarboxamide,
2-[Ethyl[2-[[2-(1H-imidazol-4-yl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-ethanol,
N2-[2-(1H-Imidazol-4-yl)ethyl]-N7,N7-dimethyl-5-[(phenylmethyl)thio]-thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-[2-(Diethylamino)ethyl]-N7-ethyl-N2-[2-(1H-imidazol-4-yl)ethyl]-5-[(phenylmethyl)thio]-thiazolo[4,5-d]pyrimidine-2,7-diamine,
N2-(2-Phenoxyethyl)-5-[(phenylmethyl)thio]-N7-(3-pyridinylmethyl)thiazolo[4,5-d]pyrimidine-2,7-diamine,
N2-(2-Phenoxyethyl)-N7-[1-(phenylmethyl)-4-piperidinyl]-5-[(phenylmethyl)thio]-thiazolo[4,5-d]pyrimidine-2,7-diamine,
2-Methyl-2-[[2-[(2-phenoxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-2-[[2-[(2-Phenoxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-4-Methyl-2-[[2-[(2-phenoxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
1-[2-[(2-Phenoxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-4-(phenylmethyl)-4-piperidinol,
2-[[2-(Cyclopropylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-[[2-(Cyclopropylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-2-[[2-(Cyclopropylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
N-[2-(Cyclopropylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-L-serine, ethyl ester,
(2R)-2-[[2-[[1-(Hydroxymethyl)butyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
N-[2-[[1-(Hydroxymethyl)butyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl-L-serine, ethyl ester,
(xc2x1)-2-[[7-[Cyclohexyl(2-hydroxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]-1-pentanol,
2-[2-[(7-(Ethylamino)-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethoxy-1-ethanol,
2-[2-[[7-[(1-Methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethoxy]-1-ethanol,
(xc2x1)-2-[[2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
2-[[2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-methyl-1-propanol,
(2R)-2-[[2-[[2-(2-Hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
2-[Cyclohexyl-[2-[[2-(2-hydroxyethoxy)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-ethanol,
(xc2x1)-2-[[5-[(Phenylmethyl)thio]-2-(4-piperidinylamino)thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-N-[2-[[7-[[1-(Hydroxymethyl)propyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-acetamide,
(xc2x1)-N-[2-[[7-[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-acetamide,
N-(2-[[7-[(2-Hydroxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-acetamide,
N-[2-[[7-[[(1R)-1-(Hydroxymethyl)-3-methylbutyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino]ethyl]-acetamide,
N7-(2-Methoxyethyl)-5-[(phenylmethyl)thio]-N2-[2-(2-thienyl)ethyl]thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-(2-Ethoxyethyl)-5-[(phenylmethyl)thio]-N2-[2-(2-thienyl)ethyl]thiazolo[4,5-d]pyrimidine-2,7-diamine,
N7-(2,2-Dimethylpropyl)-5-[(phenylmethyl)thio]-N2-[2-(2-thienyl)ethyl]thiazolo[4,5-d]pyrimidine-2,7-diamine,
(2R)-4-Methyl-2-[[-5-[(phenylmethyl)thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
(xc2x1)-1-[[5-[(Phenylmethyl)thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-2-propanol,
(xc2x1)-2-[[5-[(Phenylmethyl)thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(xc2x1)-2-[[5-[(Phenylmethyl)thio]-2-[[2-(2-thienyl)ethyl]amino]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-2-[[2-[(2-Hydroxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
(xc2x1)-N,N-Diethyl-1-[2-[(2-hydroxyethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]-3-piperidinecarboxamide,
(2R)-2-[[2-[(3-Hydroxypropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-4-methyl-1-pentanol,
(xc2x1)-2-[[2-[(3-Hydroxypropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-butanol,
(xc2x1)-2-[[2-[(3-Hydroxypropyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-[(7-[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]amino-acetamide,
4-[1-[7-[(4-Methylcyclohexyl)amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-2-yl]-3-azetidinyl]-1-piperazinesulfonamide,
3-[[2-[[2-(4-Morpholinyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
2-Methyl-2-[[2-[[2-(4-morpholinyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(xc2x1)-2-[[2-[[2-(4-Morpholinyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-propanol,
(2R)-4-Methyl-2-[[2-[[2-(4-morpholinyl)ethyl]amino]-5-[(phenylmethyl)thio]thiazolo[4,5-d]pyrimidin-7-yl]amino]-1-pentanol,
2-[[2-(3,4-Dihydroxyphenyl)ethyl]amino]-5-[(phenylmethyl)thio]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
(xc2x1)-2-[(2-Hydroxy-1-methylethyl)amino]-5-[(phenylmethyl)thio]-thiazolo[4,5-d]pyrimidin-7(4H)-one,
and their pharmaceutically acceptable salts and solvates.
According to the invention there is also provided a process for the preparation of a compound of formula (I) which comprises:
(a) when X represents xe2x80x94OH and R1 is NH2, heating a compound of general formula 
wherein R2 is as defined in formula (I); or
(b) when X represents xe2x80x94OH and R1 is NH2, reacting a compound of formula 
with a compound of general formula (IV), R2xe2x80x94L1, wherein L1 represents a leaving group such as a halogen atom (e.g. chlorine) and R2 is as defined in formula (I); or
(c) when X represents xe2x80x94OH or xe2x80x94NR13R14 and R1 is a hydrogen atom, reacting a corresponding compound of formula (I) in which R1 is NH2, with a diazotizing agent; or
(d) when X represents xe2x80x94OH and R1 is a group xe2x80x94NR3R4 reacting a compound of general formula 
wherein L2 represents a leaving group such as a halogen atom (e.g. bromine) and R2 is as defined in formula (I), with a compound of general formula (VI), R3R4NH, wherein R3 and R4 are as defined in formula (I); or
(e) when X represents xe2x80x94NR13R14 and R1 represents xe2x80x94NR3R4, reacting a compound of general formula 
wherein L3 represents a leaving group such as a halogen atom (e.g. chlorine) and R2, R3 and R4 are as defined in formula (X), with a compound of general formula (VIII), NHR13R14, wherein R13 and R14 are as defined in formula (I); or
(f) when X represents xe2x80x94NR13R14 and R1 represents xe2x80x94NR3R4, reacting a compound of general formula 
wherein L4 is a leaving group (e.g. bromine), L5 is a leaving group (e.g. chlorine) and R2 is as defined in formula (I), initially with a compound of formula (VI) as defined in (d) above followed by reaction with a compound of formula (VIII) as defined in (e) above; and optionally after (a), (b), (c), (d), (e) or (f) forming a pharmaceutically acceptable salt or solvate of the compound of formula (I).
Process (a) is conveniently carried out in the presence of a solvent or solvent mixture such as dimethylformamide/water at a temperature in the range from e.g. 50 to 150xc2x0 C.
Process (b) is conveniently carried out in an organic solvent such as tetrahydrofuran or dimethyl sulphoxide/dimethylformide mixture, optionally in the presence of a base such as potassium tert-butoxide or duisopropylamide.
Process (c) is conveniently carried out in an organic solvent such as tetrahydrofuran. Examples of suitable diazotizing agents to use include tert-butyl nitrite.
Process (d) is conveniently carried out in an organic solvent such as tetrahydrofuran, e.g. at a temperature of 50xc2x0 C. for 5 hours.
Process (e) is conveniently carried out in an organic solvent such as tetrahydrofuran with heating for a period in the range from 1 day to 3 weeks.
Process (f) is conveniently carried out in an organic solvent such as tetrahydrofuran or N-methylpyrrolidine at a temperature between 0xc2x0 and 130xc2x0 C. with a reaction time of 1 hour to 3 weeks.
Compounds of formula (II) may be readily prepared by reacting a compound of general formula 
wherein R2 is as defined above, with potassium thiocyanate and bromine in dimethylformamide/pyridine.
Compounds of formula (X) are suitably prepared by reacting a compound of formula 
with a compound of formula (IV) as defined above.
Compounds of formula (V) may be prepared by reacting a compound of formula (I) in which R1 is NH2, with a diazotizing agent and a halogenating agent. The reaction is conveniently carried out in an organic solvent such as acetonitrile in the presence of a diazotizing agent such as tert-butyl nitrite and a halogenating agent such as a trimethylsilyl halide.
Compounds of formula (VII) in which L3 is a chlorine atom may be prepared by reacting a compound of formula (I) in which X is xe2x80x94OH with phosphorus oxychloride in dimethylaniline under reflux conditions.
Compounds of formula (IX) in which L4 represents a bromine atom and L5 represents a chlorine atom may be prepared by reacting a compound of formula (I) in which X is xe2x80x94OH and R1 is NH2 with phosphorus oxychloride in dimethylaniline under reflux conditions, followed by reaction with tert-butyl nitrite and bromoform.
Compounds of formulae (III), (IV), (VI), (VIII) and (XI) are either commercially available, are well known in the literature or may be prepared easily using known techniques.
The compounds of formulae (V), (VII) and (IX) are novel intermediates and therefore form a further aspect of the present invention. In formula (V), L2 is preferably a bromine atom. In formula (VII), R3 and R4 preferably both represent a hydrogen atom. In formula (IX), L3 is preferably a bromine atom and L4 is preferably a chlorine atom.
It will be appreciated by those skilled in the art that in the processes of the present invention certain functional groups such as hydroxyl or amino groups in the starting reagents or intermediate compounds may need to be protected by protecting groups. Thus, the preparation of the compounds of formula (I) may involve, at an appropriate stage, the removal of one or more protecting groups.
The protection and deprotection of functional groups is fully described in xe2x80x98Protective Groups in Organic Chemistryxe2x80x99, edited by J. W. F. McOmie, Plenum Press (1973), and xe2x80x98Protective Groups in Organic Synthesisxe2x80x99, 2nd edition, T. W. Greene and P. G. M. Wuts, Wiley-Interscience (1991).
The compounds of formula (I) above may be converted to a phamaceutically acceptable salt or solvate thereof, preferably an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulphonate or p-toluenesulphonate.
Certain compounds of formula (I) are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention, for example tautomers of general formula 
wherein R1 and R2 are as defined in formula (I), or of general formula 
wherein R1 and R2 are as defined in formula (I).
Similarly, it will be understood that in the above processes tautomeric forms of the compounds of formulae (II), (III), (IX) and (X) may also be used, for example, 
The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of chemokine receptor (especially CXCR2) activity, and may be used in the treatment (therapeutic or prophylactic) of conditions/diseases in human and non-human animals which are exacerbated or caused by excessive or unregulated production of chemokines.
Examples of such conditions/diseases include:
(1) (the respiratory tract) obstructive airways diseases including chronic obstructive pulmonary disease (COPD) such as irreversible COPD; asthma, such as bronchial, allergic, intrinsic, extrinsic and dust asthma, particularly chronic or inveterate asthma (e.g. late asthma and airways hyper-responsiveness); bronchitis; acute, allergic, atrophic rhinitis and chronic rhinitis including rhinitis cascosa, hypertrophic rhinitis, rhinitis purulenta, rhinitis sicca and rhinitis medicamentosa; membranous rhinitis including croupous, fibrinous and pseudomembranous rhinitis and scrofoulous rhinitis; seasonal rhinitis including rhinitis nervosa (hay fever) and vasomotor rhinitis; sarcoidosis, farmer""s lung and related diseases, fibroid lung and idiopathic interstitial pneumonia;
(2) (bone and joints) rheumatoid arthritis, seronegative spondyloarthropathies (including ankylosing spondylitis, psoriatic arthritis and Reiter""s disease), Behcet""s disease, Sjogren""s syndrome and systemic sclerosis;
(3) (skin) psoriasis, atopical dermatitis, contact dermatitis and other eczmatous dermitides, seborrhoetic dermatitis, Lichen planus, Pemphigus, bullous Pemphigus, Epidermolysis bullosa, urticaria, angiodernas, vasculitides, erythemas, cutaneous eosinophilias, uveitis, Alopecia areata and vernal conjunctivitis;
(4) (gastrointestinal tract) Coeliac disease, proctitis, eosinopilic gastro-enteritis, mastocytosis, Crohn""s disease, ulcerative colitis, food-related allergies which have effects remote from the gut, e.g., migraine, rhinitis and eczema;
(5) (other tissues and systemic disease) multiple sclerosis, atherosclerosis, Acquired Immunodeficiency Syndrome (AIDS), lupus erythematosus, systemic lupus, erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, type I diabetes, nephrotic syndrome, eosinophilia fascitis, hyper IgE syndrome, lepromatous leprosy, sezary syndrome and idiopathic thrombocytopenia pupura;
(6) (allograft rejection) acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin and cornea; and chronic graft versus host disease;
(7) cancers, especially non-small cell lung cancer (NSCLC) and squamous sarcoma;
(8) diseases in which angiogenesis is associated with raised CXCR2 chemokine levels (e.g. NSCLC); and
(9) cystic fibrosis, stroke, re-perfusion injury in the heart, brain, peripheral limbs and sepsis.
Thus, the present invention provides a compound of formula (I), or a pharmaceutically-acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.
In a further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for use in therapy.
In a still further aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of human diseases or conditions in which modulation of chemokine receptor activity is beneficial.
In the context of the present specification, the term xe2x80x9ctherapyxe2x80x9d also includes xe2x80x9cprophylaxisxe2x80x9d unless there are specific indications to the contrary. The terms xe2x80x9ctherapeuticxe2x80x9d and xe2x80x9ctherapeuticallyxe2x80x9d should be construed accordingly.
The invention still further provides a method of treating a chemokine mediated disease wherein the chemokine binds to a CXCR2 receptor, which comprises administering to a patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
The invention also provides a method of treating an inflammatory disease, especially psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.
For the above-mentioned therapeutic uses the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated.
The compounds of formula (I) and pharmaceutically acceptable salts and solvates thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt/solvate (active ingredient) is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition will preferably comprise from 0.05 to 99% w (per cent by weight), more preferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w, and even more preferably from 0.10 to 50% w, of active ingredient, all percentages by weight being based on total composition.
The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
The invention further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined, with a pharmaceutically acceptable adjuvant, diluent or carrier.
The pharmaceutical compositions may be administered topically (e.g. to the lung and/or airways or to the skin) in the form of solutions, suspensions, heptafluoroalkane aerosols and dry powder formulations; or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules, or by parenteral administration in the form of solutions or suspensions, or by subcutaneous administration or by rectal administration in the form of suppositories or transdermally.
The inventon will now be further illustrated by reference to the following examples. In the examples the Nuclear Magnetic Resonance (NMR) spectra were measured on a Varian Unity Inova 300 or 400 MHz spectrometer and the Mass Spectrometry (MS) spectra measured on a Finnigan Mat SSQ7000 or Micromass Platform spectrometer. Where necessary, the reactions were performed under an inert atmosphere of either nitrogen or argon. Chromatography was generally performed using Matrex Silica 60(copyright) (35-70 micron) or Prolabo Silica gel 60(copyright) (35-70 micron) suitable for flash silica gel chromatography. High pressure liquid chromatography purification was performed using either a Waters Micromass LCZ with a Waters 600 pump controller, Waters 2487 detector and Gilson FC024 fraction collector or a Waters Delta Prep 4000. The abbreviations m.p. and DMSO used in the examples stand for melting point and dimethyl sulphoxide respectively.